Table 1.

Primary Pyruvate Dehydrogenase Complex Deficiency: Genes and Distinguishing Clinical Features

Gene 1, 2% of all PDCDDisorderDistinguishing Clinical Features
DLAT 1%-4%Pyruvate dehydrogenase E2 deficiency (OMIM 245348)
  • Milder phenotype w/survival into childhood/adulthood
  • Episodic dystonia
  • PDC enzyme activity below reference range but not as low as other forms of PDCD
  • ± abnl brain MRI, globus pallidus lesions (resembles PKAN but w/o "eye of the tiger" MRI sign)
  • Several w/clinical response to lipoic acid, thiamine, &/or ketogenic diet
DLD 1%-6% Dihydrolipoamide dehydrogenase deficiency
  • Present w/Leigh syndrome 3 or w/intermittent liver failure
  • ↑ branched-chain amino acids (i.e., mild-moderate ↑s of leucine, isoleucine & valine w/or w/o alloisoleucine)
  • ↑ citrulline
  • ↑ urine alpha-ketoglutarate
  • Founder variant in Ashkenazi Jewish population 4
PDHA1 76%-85%Pyruvate dehydrogenase E1-alpha deficiency (OMIM 312170)
  • Variable phenotype: neonatal lactic acidosis, Leigh syndrome 3, or adult-onset myopathy or ataxia
  • Affected females have most striking abnormalities on brain MRI (e.g., asymmetric ventriculomegaly, corpus callosum dysgenesis).
  • Variable response to ketogenic diet; treatment w/ketogenic diet is assoc w/↑ life span. 5
PDHB 4%-9%Pyruvate dehydrogenase E1-beta deficiency (OMIM 614111)
  • Typically more severely affected
  • ± structural brain abnormalities & microcephaly
  • Leigh syndrome 3 & neonatal lactic acidosis
  • IUGR
  • Treatment w/ketogenic diet is assoc w/↑ life span.
PDHX 7%-11%Pyruvate dehydrogenase E3-binding protein deficiency (OMIM 245349)
  • Neonatal lactic acidosis
  • Non-progressive encephalopathy
  • Mild dysmorphic features
  • Founder variant in people of Roma & Moroccan ancestry 6
PDP1 ~1%Pyruvate dehydrogenase phosphatase deficiency (OMIM 608782)
  • Cardiomyopathy
  • Neonatal lactic acidosis
  • Clinical response to ketogenic diet
PDK3 <1%CMT, X-linked dominant type 6 (OMIM 300905)
  • Clinical features of CMT incl pes cavus foot deformity & hand wasting
  • Childhood/adult onset

abnl = abnormal; CMT = Charcot-Marie-Tooth; IUGR = intrauterine growth restriction; PKAN = pantothenate kinase-associated neurodegeneration


Genes are listed alphabetically


Molecular causes of secondary pyruvate dehydrogenase deficiency are discussed in Table 2.


Leigh syndrome is characterized by decompensation during intercurrent illness, lactic acidosis, and bilateral symmetric T2-weighted hyperintensities in the basal ganglia and/or brain stem on brain MRI.


DLD pathogenic variant c.685G>T (p.Gly229Cys) is an Ashkenazi-Jewish founder variant.


PDHX c.1336C>T (p.Arg446Ter) is a Roma founder variant; c.1182+2T>C (p.Ile386SerfsTer13) is a Moroccan founder variant.

From: Primary Pyruvate Dehydrogenase Complex Deficiency Overview

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